EP0153615B1 - Process for the preparation of tetronic acid - Google Patents
Process for the preparation of tetronic acid Download PDFInfo
- Publication number
- EP0153615B1 EP0153615B1 EP85101150A EP85101150A EP0153615B1 EP 0153615 B1 EP0153615 B1 EP 0153615B1 EP 85101150 A EP85101150 A EP 85101150A EP 85101150 A EP85101150 A EP 85101150A EP 0153615 B1 EP0153615 B1 EP 0153615B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- ester
- hydrogenation
- converted
- tetronic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Definitions
- the invention relates to a process for the preparation of tetronic acid from 2,4-dichloroacetoacetic esters.
- CH-PS 503 722 for example, 4-chloroacetoacetic ester is reacted with an aromatic amine to give 3-arylaminocrotolactone and the tetronic acid is liberated therefrom by treatment with mineral acids.
- the disadvantage of this method is that tetronic acid can only be isolated by high vacuum sublimation.
- CH-PS 529 128, 4-haloacetoacetic acid is used, which is reacted with alkalis in aqueous solution. Treatment with mineral acids releases the tetronic acid.
- the tetronic acid must be isolated by high-vacuum sublimation, and the yield that can be achieved is only 43 to 44%.
- a 4-haloacetoacetic ester is first converted into the corresponding 4-benzyloxyacetoacetic ester and the corresponding 4-hydroxyacetoacetic ester is formed from this as an intermediate product by hydrogenolysis, which is converted into the tetronic acid by treatment with acid.
- the 4-hydroxyacetoacetic ester can be isolated and, after isolation, the treatment with acid can be carried out.
- the 4-hydroxyacetoacetic ester formed primarily in situ is converted directly into the tetronic acid. The disadvantage of this process is that it has to be carried out over complex intermediate products.
- a further disadvantage of this process is that the tetronic acid can only be obtained by lengthy extraction as a result of organic salts.
- the aim of the present invention is to avoid the disadvantages of the known methods.
- esters can be used as 4-chloroacetoacetic esters. Those of alcohols having 1 to 6 carbon atoms or benzyl esters are suitable. The 4-chloroacetoacetic acid ethyl ester is preferably used.
- the chlorination to 2,4-dichloroester can be carried out according to known methods.
- the chlorination is e.g. B. carried out using sulfuryl chloride in an organic solvent or solvent mixture.
- Chlorinated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or aromatic hydrocarbons such as u. a. Toluene, but methylene chloride is preferably used.
- methylene chloride is preferably used.
- 200 to 1000 g of solvent are used per mole of 4-chloroacetoacetic ester.
- the molar ratio of chlorinating agent to 4-chloroacetoacetic ester is preferably 1 to 1.
- the temperatures at which the chlorination is carried out can vary, but it is expedient to work at 0 to 40 ° C.
- the 2,4-dichloro ester obtained after chlorination is dissolved in the solvent. Before further processing, this 2,4-dichloroester is advantageously freed from the solvent and subjected to the thermal treatment.
- the procedure is such that the 2,4-dichloroester is dried after removal of the solvent and heated at 110 to 160 ° C, preferably at 130 to 150 ° C.
- This thermal treatment is advantageously carried out under reflux conditions at reduced pressure or normal pressure, preferably normal pressure.
- the 3-chlorotetronic acid present as the solidified product is advantageously purified with an aromatic hydrocarbon and then subjected to the hydrogenation.
- the hydrogenation expediently takes place in water.
- the aqueous solution of 3-chlorotetronic acid in the presence of a platinum catalyst such as platinum, palladium or rhodium, in particular in amounts of 2 to 10% on a support material such as pumice, clay, silica gel or carbon with hydrogen, under pressure at temperatures of 0 hydrogenated up to 30 ° C. It is preferred to work with 5% palladium on carbon at room temperature.
- the hydrogenation pressure can be between 3.5 and 20 atm, whereby low pressures mean longer hydrogenation times.
- 3.0 to 8.0 g, preferably 4.0 g, of the palladium catalyst are used per mole of 3-chiortetronic acid.
- the 2,4-dichloroacetoacetic ester can be prepared almost quantitatively from the commercially available 4-chloroacetoacetic ester and requires no purification by distillation for further implementation.
- the 2,4-dichloroacetoacetic acid ethyl ester was heated under reflux at 140 ° C. for 2.5 hours. This boiling temperature was achieved by carrying out the reaction under reduced pressure. Since the 2,4-dichloroacetoacetic ester was consumed during the reaction, a constant reaction temperature was only obtained by continuously reducing the pressure (beginning 90 mbar to end 30 mbar). The reaction was complete when no reflux was observed. The reaction mixture was allowed to cool, the solution solidifying. This mixture was made again stirrable by adding 300 ml of toluene. The precipitated 3-chlorotetronic acid was filtered off with suction, washed with 500 ml of toluene and dried in a high vacuum.
- the mother liquor of the reaction solution was evaporated and distilled in a high vacuum.
- Example 2 As in Example 1, 1 mol of 4-chloroacetoacetic acid methyl ester was chlorinated with equivalent amounts of sulfuryl chloride at room temperature. The conversion to the 2,4-dichloroacetoacetic acid methyl ester was quantitative, the content (GC) was 93%. Subsequent heating under reflux at 140 ° C. for 3 hours in vacuo (95 to 70 mm Hg) gave the 3-chlorotetronic acid in 75.5% yield , with a content of 100%.
- Example 1 As in Example 1, 1 mol of 4-chloroacetoacetic acid ethyl ester was chlorinated with equivalent amounts of sulfuryl chloride at room temperature. The conversion to the 2,4-dichloroacetoacetic acid ethyl ester was quantitative, the content (GC) was 96%. Subsequent heating for 4 hours at 140 ° C. under normal pressure gave the 3-chlorotetronic acid in a yield of 84.6% with a content of 100%. After further conversion to the tetronic acid according to Example 1, the tetronic acid was obtained in a total yield, based on ethyl 4-chloroacetoacetate, of 74%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von Tetronsäure aus 2,4-Dichloracetessigestern.The invention relates to a process for the preparation of tetronic acid from 2,4-dichloroacetoacetic esters.
Es ist -bekannt, Tetronsäure ausgehend von Acetessigester über den 2,4-Dibromacetessigester und die 3-Bromtetronsäure mit anschliessender Hydrierung mit Natriumamalgan herzustellen [Wolff und .Schwabe, Ann. 291 (1896), 231, und W. D. Kumler, J. Am. Chem. Soc. 60 (1938) 863]. Die Ausbeute an Tetronsäure, bezogen auf das Ausgangsmaterial, lag bei 18 %.It is known to produce tetronic acid starting from acetoacetic ester via the 2,4-dibromoacetoacetic ester and 3-bromotetronic acid with subsequent hydrogenation with sodium amalgan [Wolff and. Schwabe, Ann. 291 (1896), 231, and W. D. Kumler, J. Am. Chem. Soc. 60 (1938) 863]. The yield of tetronic acid, based on the starting material, was 18%.
Da dieses Verfahren unbefriedigend war, wurden eine ganze Reihe anderer Verfahren entwickelt. Nach CH-PS 503 722 beispielsweise wird 4-Chloracetessigester mit einem aromatischen Amin zum 3-Arylaminocrotolacton umgesetzt und aus diesem durch Behandlung mit Mineralsäuren die Tetronsäure in Freiheit gesetzt. Der Nachteil dieser Methode besteht darin, dass die Isolierung der Tetronsäure nur durch Hochvakuumsublimation zu realisieren ist. Nach CH-PS 529 128 wird von 4-Halogenacetessigsäure ausgegangen, die in wässriger Lösung mit Alkalien umgesetzt wird. Durch Behandeln mit Mineralsäuren wird die Tetronsäure in Freiheit gesetzt. Auch hier muss die Isolierung der Tetronsäure über eine Hochvakuumsublimation erfolgen, ausserdem ist die erzielbare Ausbeute nur 43 bis 44 %.Since this process was unsatisfactory, a number of other processes have been developed. According to CH-PS 503 722, for example, 4-chloroacetoacetic ester is reacted with an aromatic amine to give 3-arylaminocrotolactone and the tetronic acid is liberated therefrom by treatment with mineral acids. The disadvantage of this method is that tetronic acid can only be isolated by high vacuum sublimation. According to CH-PS 529 128, 4-haloacetoacetic acid is used, which is reacted with alkalis in aqueous solution. Treatment with mineral acids releases the tetronic acid. Here too, the tetronic acid must be isolated by high-vacuum sublimation, and the yield that can be achieved is only 43 to 44%.
Nach US-PS 44 21 922 wird zunächst ein 4-Halogenacetessigester in den entsprechenden 4-Benzyloxyacetessigester überführt und aus diesem durch Hydrogenolyse als Zwischenprodukt der entsprechende 4-Hydroxyacetessigester gebildet, der durch Behandeln mit Säure in die Tetronsäure überführt wird. Bei diesem Verfahren kann der 4-Hydroxyacetessigester isoliert werden und nach Isolation die Behandlung mit Säure durchgeführt werden. Es ist aber auch möglich, die Hydrogenolyse in Gegenwart von Säure durchzuführen. Dabei wird der primär in situ gebildete 4-Hydroxyacetessigester unmittelbar in die Tetronsäure überführt. Der Nachteil dieses Verfahrens liegt darin, dass es über aufwendige Zwischenprodukte geführt werden muss. Grob, Schmidt und Zimmer haben dann wieder versucht, die Tetronsäuresynthese ausgehend von Acetessigester über die 3-Bromtetronsäure zu verbessern (Syn. Comm. 11 (5) 1981, 385-390). Dabei wurde die Bromierung des Acetessigesters und die Umsetzung dieses Produkte zu 3-Bromtetronsäure nach W. D. Kumler [J. Am. Chem. Soc. 60 (1938) 859] durchgeführt, die Hydrierung aber mittels H2 und Pd/C vorgenommen. Die Verbesserung liegt in dieser Stufe, wird doch eine Ausbeute von 82 bis 94 % erreicht. Diese Ausbeute ist aber auf die 3-Bromtetronsäure bezogen. Bezieht man sie aber auf die gesamte Reaktion, also einschliesslich der Synthese der 3-Bromtetronsäure aus Acetessigester (nach Kumler etwa 36 %), so liegt sie auch nur bei 29 bis 34 %.According to US Pat. No. 4,421,922, a 4-haloacetoacetic ester is first converted into the corresponding 4-benzyloxyacetoacetic ester and the corresponding 4-hydroxyacetoacetic ester is formed from this as an intermediate product by hydrogenolysis, which is converted into the tetronic acid by treatment with acid. In this process, the 4-hydroxyacetoacetic ester can be isolated and, after isolation, the treatment with acid can be carried out. However, it is also possible to carry out the hydrogenolysis in the presence of acid. The 4-hydroxyacetoacetic ester formed primarily in situ is converted directly into the tetronic acid. The disadvantage of this process is that it has to be carried out over complex intermediate products. Grob, Schmidt and Zimmer then tried again to improve tetronic acid synthesis starting from acetoacetic ester via 3-bromotetronic acid (Syn. Comm. 11 (5) 1981, 385-390). The bromination of the acetoacetic ester and the conversion of this product to 3-bromotetronic acid according to WD Kumler [J. At the. Chem. Soc. 60 (1938) 859], but the hydrogenation was carried out using H 2 and Pd / C. The improvement lies in this stage, since a yield of 82 to 94% is achieved. However, this yield is based on the 3-bromotetronic acid. However, if you refer to the entire reaction, including the synthesis of 3-bromotetronic acid from acetoacetic ester (according to Kumler, about 36%), it is only 29 to 34%.
Ein weiterer Nachteil dieses Verfahrens besteht darin, dass infolge anfallender organischer Salze die Tetronsäure nur durch langwierige Extraktion gewonnen werden kann.A further disadvantage of this process is that the tetronic acid can only be obtained by lengthy extraction as a result of organic salts.
Ziel der vorliegenden Erfindung ist es, die Nachteile der bekannten Verfahren zu vermeiden.The aim of the present invention is to avoid the disadvantages of the known methods.
Erreicht wird dies erfindungsgemäss durch ein Verfahren gemäss Anspruch 1.This is achieved according to the invention by a method according to claim 1.
Als 4-Chloracetessigester können prinzipiell alle Ester verwendet werden. Zweckmässig kommen solche von Alkoholen mit 1 bis 6 C-Atomen oder Benzylester in Frage. Vorzugsweise wird der 4-Chloracetessigsäureäthylester verwendet.In principle, all esters can be used as 4-chloroacetoacetic esters. Those of alcohols having 1 to 6 carbon atoms or benzyl esters are suitable. The 4-chloroacetoacetic acid ethyl ester is preferably used.
Die Chlorierung zum 2,4-Dichlorester kann nach bekannten Methoden durchgeführt werden. Vorzugsweise wird die Chlorierung z. B. mittels Sulfurylchlorid in einem organischen Lösungsmittel oder Lösungsmittelgemisch durchgeführt.The chlorination to 2,4-dichloroester can be carried out according to known methods. Preferably the chlorination is e.g. B. carried out using sulfuryl chloride in an organic solvent or solvent mixture.
Als Lösungsmittel werden chlorierte aliphatische Kohlenwasserstoffe, wie Methylenchlorid, Chloroform, Tetrachlorkohlenstoff oder aromatische Kohlenwasserstoffe, wie u. a. Toluol, angewendet, vorzugsweise wird aber Methylenchlorid verwendet. Zweckmässig setzt man pro Mol 4-Chloracetessigester 200 bis 1000 g Lösungsmittel ein.Chlorinated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or aromatic hydrocarbons such as u. a. Toluene, but methylene chloride is preferably used. Appropriately, 200 to 1000 g of solvent are used per mole of 4-chloroacetoacetic ester.
Das Molverhältnis Chlorierungsmittel zu 4-Chloracetessigester beträgt vorzugsweise 1 zu 1.The molar ratio of chlorinating agent to 4-chloroacetoacetic ester is preferably 1 to 1.
Die Temperaturen, bei welcher die Chlorierung durchgeführt wird, kann variieren, doch wird zweckmässig bei 0 bis 40 °C gearbeitet.The temperatures at which the chlorination is carried out can vary, but it is expedient to work at 0 to 40 ° C.
Der nach der Chlorierung anfallende 2,4-Dichlörester liegt gelöst im Lösungsmittel vor. Vor der Weiterverarbeitung wird dieser 2,4-Dichlorester vorteilhaft vom Lösungsmittel befreit und der thermischen Behandlung unterworfen.The 2,4-dichloro ester obtained after chlorination is dissolved in the solvent. Before further processing, this 2,4-dichloroester is advantageously freed from the solvent and subjected to the thermal treatment.
Zweckmässig wird so vorgegangen, dass der 2,4-Dichlorester nach Abzug des Lösungsmittels getrocknet und bei 110 bis 160 °C, vorzugsweise bei 130 bis 150 °C, erhitzt wird. Diese thermische Behandlung wird zweckmäßig unter Rückflussbedingungen bei vermindertem Druck oder Normaldruck, vorzugsweise Normaldruck, durchgeführt.Appropriately, the procedure is such that the 2,4-dichloroester is dried after removal of the solvent and heated at 110 to 160 ° C, preferably at 130 to 150 ° C. This thermal treatment is advantageously carried out under reflux conditions at reduced pressure or normal pressure, preferably normal pressure.
Nach beendeter Reaktion wird die als erstarrtes Produkt vorliegende 3-Chlortetronsäure vorteilhaft mit einem aromatischen Kohlenwasserstoff gereinigt und anschliessend der Hydrierung unterworfen.After the reaction has ended, the 3-chlorotetronic acid present as the solidified product is advantageously purified with an aromatic hydrocarbon and then subjected to the hydrogenation.
Die Hydrierung findet zweckmäßig in Wasser statt. Dazu wind die wässrige Lösung der 3-Chlortetronsäure in Gegenwart eines Platinkatalysators, wie Platin, Palladium oder Rhodium, insbesondere in Mengen von 2 bis 10 % auf einem Trägermaterial, wie Bimsstein, Tonerde, Silicagel oder Kohle mit Wasserstoff, unter Druck bei Temperaturen von 0 bis 30 °C hydriert. Vorzugsweise wird mit 5 % Palladium auf Kohle bei Raumtemperatur gearbeitet.The hydrogenation expediently takes place in water. For this purpose, the aqueous solution of 3-chlorotetronic acid in the presence of a platinum catalyst such as platinum, palladium or rhodium, in particular in amounts of 2 to 10% on a support material such as pumice, clay, silica gel or carbon with hydrogen, under pressure at temperatures of 0 hydrogenated up to 30 ° C. It is preferred to work with 5% palladium on carbon at room temperature.
Der Hydrierdruck kann zwischen 3,5 und 20 atm liegen, wobei niedrige Drücke längere Hydrierzeiten bedeuten.The hydrogenation pressure can be between 3.5 and 20 atm, whereby low pressures mean longer hydrogenation times.
Zweckmässig werden pro Mol 3-Chiortetronsäure 3,0 bis 8,0 g, vorzugsweise 4,0 g, des Palladiumkatalysators verwendet.Advantageously, 3.0 to 8.0 g, preferably 4.0 g, of the palladium catalyst are used per mole of 3-chiortetronic acid.
Das erfindungsgemässe Verfahren hat gegenüber den bekannten Verfahren des Standes der Technik folgende Vorteile :The method according to the invention has the following advantages over the known methods of the prior art:
Der 2,4-Dichloracetessigester lässt sich nahezu quantitativ aus dem grosstechnisch verfügbaren 4-Chloracetessigester darstellen und bedarf keiner destillativen Reinigung für die weitere Umsetzung.The 2,4-dichloroacetoacetic ester can be prepared almost quantitatively from the commercially available 4-chloroacetoacetic ester and requires no purification by distillation for further implementation.
Die Ausbeute an 3-Chlortetronsäure (65 bis 75 %) bei der thermischen Cyclisierung des 2,4-Dichloracetessigesters ist doppelt so hoch wie diejenige an 3-Bromtetronsäure aus dem entsprechenden Dibromester.The yield of 3-chlorotetronic acid (65 to 75%) in the thermal cyclization of the 2,4-dichloroacetoacetic ester is twice as high as that of 3-bromotetronic acid from the corresponding dibromoester.
Bei der Reduktion der 3-Chlortetronsäure zur Tetronsäure kann ohne Zusatz von Basen gearbeitet werden. Somit entfällt eine aufwendige Trennung von Tetronsäure und anorganischen Salzen.The reduction of 3-chlorotetronic acid to tetronic acid can be carried out without the addition of bases. This eliminates the time-consuming separation of tetronic acid and inorganic salts.
335,90 g (2,00 Mol) 4-Chloracetessigsäureäthylester wurden in 1000 ml Methylenchlorid gelöst. Dazu wurden bei Raumtemperatur innerhalb von 2,5 Std 287,12 g (2,04 Mol) Sulfurylchlorid langsam zugetropft. Die Gasentwicklung war nach ca. 10 Std beendet. Anschliessend wurde das Lösungsmittel am Rotationsverdampfer abdestilliert und das gelbe ölige Reaktionsprodukt am Hochvakuum getrocknet.335.90 g (2.00 mol) of ethyl 4-chloroacetoacetate were dissolved in 1000 ml of methylene chloride. 287.12 g (2.04 mol) of sulfuryl chloride were slowly added dropwise at room temperature over the course of 2.5 hours. The gas evolution ended after about 10 hours. The solvent was then distilled off on a rotary evaporator and the yellow oily reaction product was dried in a high vacuum.
Man erhielt 405,30 g 2,4-Dichloracetessigsäureäthylester mit einem Gehalt (GC) von 96,1 %.This gave 405.30 g of ethyl 2,4-dichloroacetoacetate with a content (GC) of 96.1%.
Der 2,4-Dichloracetessigsäureäthylester wurde 2,5 Std bei 140 °C unter Rückfluss erhitzt. Diese Siedetemperatur erreichte man dadurch, dass die Reaktion unter vermindertem Druck durchgeführt wurde. Da sich der 2,4-Dichloracetessigester während der Reaktion verbrauchte, erhielt man eine konstante Reaktionstemperatur nur durch kontinuierliche Verkleinerung des Druckes (Anfang 90 mbar bis Ende 30 mbar). Die Reaktion war beendet, als kein Rückfluss mehr beobachtet wurde. Man liess das Reaktionsgemisch abkühlen, wobei die Lösung erstarrte. Durch Zugabe von 300 ml Toluol wurde dieses Gemisch wieder rührbar gemacht. Die ausgefallene 3-Chlortetronsäure wurde abgenutscht, mit 500 ml Toluol gewaschen und am Hochvakuum getrocknet. Man erhielt 185,20 g schwach bräunlich gefärbte, mikrokristalline 3-Chlortetronsäure vom Smp. 206 °C, deren Gehalt laut potentiometrischer NaOH-Titration 99,3 % betrug. Dies entsprach einer Ausbeute von 68,4 %, bezogen auf 100 %igen 4-Chloracetessigsäureäthylester. Zur Umkristallisation wurden 170 g 3-Chlortetronsäure in 3400 ml Essigester heiss gelöst und mit 20 g Aktivkohle 2 Std unter Rückfluss gekocht. Die heisse Lösung wurde abfiltriert und die gelblich gefärbte Lösung auf 100 ml eingeengt. Der ausgefallene Niederschlag wurde abgesaugt, mit 100 ml Essigester gewaschen und am Hochvakuum getrocknet. Man isolierte 166 g weisse, mikrokristalline 3-Chlortetronsäure vom Smp. 206 °C mit einem Gehalt von 99,4 %.The 2,4-dichloroacetoacetic acid ethyl ester was heated under reflux at 140 ° C. for 2.5 hours. This boiling temperature was achieved by carrying out the reaction under reduced pressure. Since the 2,4-dichloroacetoacetic ester was consumed during the reaction, a constant reaction temperature was only obtained by continuously reducing the pressure (beginning 90 mbar to end 30 mbar). The reaction was complete when no reflux was observed. The reaction mixture was allowed to cool, the solution solidifying. This mixture was made again stirrable by adding 300 ml of toluene. The precipitated 3-chlorotetronic acid was filtered off with suction, washed with 500 ml of toluene and dried in a high vacuum. 185.20 g of slightly brownish-colored, microcrystalline 3-chlorotetronic acid with a melting point of 206 ° C. were obtained, the content of which according to potentiometric NaOH titration was 99.3%. This corresponded to a yield of 68.4%, based on 100% ethyl 4-chloroacetoacetate. For recrystallization, 170 g of hot 3-chlorotetronic acid were dissolved in 3400 ml of ethyl acetate and boiled under reflux with 20 g of activated carbon for 2 hours. The hot solution was filtered off and the yellowish solution was concentrated to 100 ml. The precipitate was filtered off, washed with 100 ml of ethyl acetate and dried in a high vacuum. 166 g of white, microcrystalline 3-chlorotetronic acid with a melting point of 206 ° C. were isolated with a content of 99.4%.
Die Mutterlauge der Reaktionslösung wurde eingedampft und am Hochvakuum destilliert.The mother liquor of the reaction solution was evaporated and distilled in a high vacuum.
Aus der ersten Fraktion wurden 12,48 g unumgesetzter 2,4-Dichloracetessigester zurückgewonnen.12.48 g of unreacted 2,4-dichloroacetoacetic ester were recovered from the first fraction.
50,0 g (0,37 Mol) 3-Chlortetronsäure (Gehalt 99,4 %) wurden in 400 ml Wasser gelöst und mit 1,45 g Palladium auf Kohle 5 % versetzt. Man hydrierte bei einem Anfangsdruck von 5 bar und Raumtemperatur. Nach 7 Std war die Wasserstoffabsorption beendet. Man filtrierte vom Katalysator ab, wusch mit 100 ml Wasser nach und destillierte das Wasser am Rotationsverdampfer bei einer Badtemperatur von maximal 30 °C ab. Die leicht gelbliche Rohsäure wurde 3 Std am Hochvakuum getrocknet.50.0 g (0.37 mol) of 3-chlorotetronic acid (99.4% content) were dissolved in 400 ml of water and 1.45 g of palladium on carbon 5% were added. The mixture was hydrogenated at an initial pressure of 5 bar and room temperature. The hydrogen absorption was complete after 7 hours. The catalyst was filtered off, washed with 100 ml of water and the water was distilled off on a rotary evaporator at a bath temperature of at most 30 ° C. The slightly yellowish crude acid was dried under high vacuum for 3 hours.
Ausbeute : 36,5 g weisse kristalline Tetronsäure.Yield: 36.5 g of white crystalline tetronic acid.
Gehalt (HPLC) 99,2 %.Content (HPLC) 99.2%.
Die Gesamtausbeute an Tetronsäure, bezogen auf eingesetzten 4-Chloracetessigäthylester betrug 65,6 %.The overall yield of tetronic acid, based on the 4-chloroacetoacetate used, was 65.6%.
Wie in Beispiel 1 wurde 1 Mol 4-Chloracetessigsäuremethylester mit äquivalenten Mengen Sulfurylchlorid bei Raumtemperatur chloriert. Die Umsetzung zum 2,4-Dichloracetessigsäuremethylester war quantitativ, der Gehalt (GC) betrug 93 % Nachfolgendes 3-stündiges Erhitzen unter Rückfluss bei 140 °C im Vakuum (95 bis 70 mm Hg) lieferte die 3-Chlortetronsäure in 75,5 % Ausbeute, mit einem Gehalt von 100 %.As in Example 1, 1 mol of 4-chloroacetoacetic acid methyl ester was chlorinated with equivalent amounts of sulfuryl chloride at room temperature. The conversion to the 2,4-dichloroacetoacetic acid methyl ester was quantitative, the content (GC) was 93%. Subsequent heating under reflux at 140 ° C. for 3 hours in vacuo (95 to 70 mm Hg) gave the 3-chlorotetronic acid in 75.5% yield , with a content of 100%.
Die Aufarbeitung erfolgte wie in Beispiel 1. Bei der Destillation der Mutterlauge erhielt man 11,8 % Edukt zurück.Working up was carried out as in Example 1. The distillation of the mother liquor gave back 11.8% of starting material.
Wie in Beispiel 1 wurde 1 Mol 4-Chloracetessigsäurebenzylester mit äquivalenten Mengen Sulfurylchlorid bei Raumtemperatur chloriert. Die Umsetzung zum 2,4-Dichloracetessigsäurebenzylester war quantitativ.As in Example 1, 1 mol of 4-chloroacetoacetic acid benzyl ester was chlorinated with equivalent amounts of sulfuryl chloride at room temperature. The conversion to benzyl 2,4-dichloroacetoacetate was quantitative.
Nachfolgendes 2-stündiges Erhitzen unter Rückfluss bei 130 °C im Vakuum (25 bis 60 mm Hg) lieferte die 3-Chlortetronsäure in 66,3 % Ausbeute, mit einem Gehalt von 99,9 %.Subsequent heating under reflux at 130 ° C. in vacuo (25 to 60 mm Hg) gave the 3-chlorotetronic acid in 66.3% yield, with a content of 99.9%.
Wie in Beispiel 1 wurde 1 Mol 4-Chloracetessigsäureethylester mit äquivalenten Mengen Sulfurylchlorid bei Raumtemperatur chloriert. Die Umsetzung zum 2,4-Dichloracetessigsäureethylester war quantitativ, der Gehalt (GC) betrug 96 %. Nachfolgendes 4-stündiges Erhitzen bei 140 °C bei Normaldruck lieferte die 3-Chlortetronsäure in einer Ausbeute von 84,6 % mit einem Gehalt von 100 %. Nach Weiterumsetzung zur Tetronsäure gemäß Beispiel 1 wurde die Tetronsäure in einer Gesamtausbeute, bezogen auf 4-Chloracetessigsäureethylester, von 74 % erhalten.As in Example 1, 1 mol of 4-chloroacetoacetic acid ethyl ester was chlorinated with equivalent amounts of sulfuryl chloride at room temperature. The conversion to the 2,4-dichloroacetoacetic acid ethyl ester was quantitative, the content (GC) was 96%. Subsequent heating for 4 hours at 140 ° C. under normal pressure gave the 3-chlorotetronic acid in a yield of 84.6% with a content of 100%. After further conversion to the tetronic acid according to Example 1, the tetronic acid was obtained in a total yield, based on ethyl 4-chloroacetoacetate, of 74%.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH604/84A CH658056A5 (en) | 1984-02-09 | 1984-02-09 | METHOD FOR PRODUCING TETRONIC ACID. |
| CH604/84 | 1984-02-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0153615A1 EP0153615A1 (en) | 1985-09-04 |
| EP0153615B1 true EP0153615B1 (en) | 1989-04-26 |
Family
ID=4190834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP85101150A Expired EP0153615B1 (en) | 1984-02-09 | 1985-02-04 | Process for the preparation of tetronic acid |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0153615B1 (en) |
| JP (1) | JPS60184073A (en) |
| AT (1) | ATE42550T1 (en) |
| CA (1) | CA1225094A (en) |
| CH (1) | CH658056A5 (en) |
| DD (1) | DD229126A5 (en) |
| DE (1) | DE3569735D1 (en) |
| HU (1) | HU196066B (en) |
| IL (1) | IL74131A (en) |
| IN (1) | IN162567B (en) |
| MX (1) | MX156171A (en) |
| SU (1) | SU1436868A3 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63112883U (en) * | 1987-01-13 | 1988-07-20 | ||
| JPH0525919Y2 (en) * | 1987-11-30 | 1993-06-30 | ||
| CA2211503A1 (en) * | 1996-09-04 | 1998-03-04 | Josef Schroer | Process for the preparation of tetronic acid derivatives |
| CA2210821A1 (en) * | 1996-09-04 | 1998-03-04 | Lonza Ag | Process for the preparation of an arylazotetronic acid derivative |
| AUPQ841900A0 (en) * | 2000-06-28 | 2000-07-20 | Unisearch Limited | Synthesis of cyclic compounds |
| EP2042496A1 (en) | 2007-09-18 | 2009-04-01 | Bayer CropScience AG | Method for manufacturing 4-aminobut-2-enolids |
| EP2039678A1 (en) | 2007-09-18 | 2009-03-25 | Bayer CropScience AG | Method for manufacturing 4-aminobut-2-enolids |
| JP2010070460A (en) | 2008-09-16 | 2010-04-02 | Daicel Chem Ind Ltd | Method for producing tetronic acid |
| EP2230237A1 (en) | 2009-03-16 | 2010-09-22 | Bayer CropScience AG | New method for producing enaminocarbonyl compounds |
| EP2230236A1 (en) | 2009-03-16 | 2010-09-22 | Bayer CropScience AG | New method for producing enaminocarbonyl compounds |
| TW201111370A (en) | 2009-08-18 | 2011-04-01 | Bayer Cropscience Ag | Novel process for the preparation of 4-aminobut-2-enolides |
| JP5766715B2 (en) | 2009-12-23 | 2015-08-19 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | Novel process for the preparation of 4-aminobut-2-enolides starting from 4-alkoxyfuran-2 (5H) -one or 4-arylalkoxyfuran-2 (5H) -one |
| CN106632081A (en) * | 2016-12-14 | 2017-05-10 | 四川同晟生物医药有限公司 | 5-chloro-6-(chloromethyl) uracil and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH529128A (en) * | 1970-09-04 | 1972-10-15 | Lonza Ag | Process for the production of tetronic acid |
| CH649996A5 (en) * | 1981-06-17 | 1985-06-28 | Lonza Ag | PROCESS FOR THE PRODUCTION OF TETRONIC ACID. |
| CH649294A5 (en) * | 1981-06-17 | 1985-05-15 | Lonza Ag | METHOD FOR PRODUCING TETRONIC ACID. |
-
1984
- 1984-02-09 CH CH604/84A patent/CH658056A5/en not_active IP Right Cessation
-
1985
- 1985-01-14 HU HU85132A patent/HU196066B/en not_active IP Right Cessation
- 1985-01-18 DD DD85272648A patent/DD229126A5/en not_active IP Right Cessation
- 1985-01-22 IN IN52/MAS/85A patent/IN162567B/en unknown
- 1985-01-22 IL IL74131A patent/IL74131A/en unknown
- 1985-02-04 EP EP85101150A patent/EP0153615B1/en not_active Expired
- 1985-02-04 AT AT85101150T patent/ATE42550T1/en not_active IP Right Cessation
- 1985-02-04 DE DE8585101150T patent/DE3569735D1/en not_active Expired
- 1985-02-06 MX MX204247A patent/MX156171A/en unknown
- 1985-02-07 CA CA000473780A patent/CA1225094A/en not_active Expired
- 1985-02-08 SU SU853853848A patent/SU1436868A3/en active
- 1985-02-08 JP JP60023386A patent/JPS60184073A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH658056A5 (en) | 1986-10-15 |
| HU196066B (en) | 1988-09-28 |
| SU1436868A3 (en) | 1988-11-07 |
| JPS6156232B2 (en) | 1986-12-01 |
| ATE42550T1 (en) | 1989-05-15 |
| HUT39441A (en) | 1986-09-29 |
| JPS60184073A (en) | 1985-09-19 |
| DE3569735D1 (en) | 1989-06-01 |
| MX156171A (en) | 1988-07-19 |
| DD229126A5 (en) | 1985-10-30 |
| IN162567B (en) | 1988-06-11 |
| IL74131A0 (en) | 1985-04-30 |
| EP0153615A1 (en) | 1985-09-04 |
| IL74131A (en) | 1988-11-30 |
| CA1225094A (en) | 1987-08-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0153615B1 (en) | Process for the preparation of tetronic acid | |
| EP0847990A1 (en) | 4-(C1-C4)-Alkoxy-3-pyrrolin-2-on-1-yl-acetic acid derivatives, their preparation and use in the synthesis of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide | |
| DE2609015C2 (en) | Process for the preparation of Benz (f) -2,5-oxazocines | |
| CH629189A5 (en) | METHOD FOR PRODUCING 2- (2,2-DICYCLOHEXYLETHYL) PIPERIDINE. | |
| DE3871591T2 (en) | METHOD FOR PRODUCING 1-PROPARGYL-2,4-DIOXOIMIDAZOLIDINE. | |
| DE2107411A1 (en) | Process for the preparation of dipeptides containing alpha asparagmyl radicals | |
| DE2721265C2 (en) | Process for the preparation of di-n-propylacetonitrile | |
| DE2166997C3 (en) | Process for the preparation of 4,4-diphenyl-piperidines | |
| DE2461307B2 (en) | 2-Hydroxymethyl-3-hydroxypyridine-6-epoxyethane derivatives, process for their preparation and their use for the preparation of 2-hydroxymethyl-3hydroxy-6- (1-hydroxy-2-tert.butylaminoethyopyridine | |
| CH652388A5 (en) | METHOD FOR PRODUCING propafenone. | |
| DE2034682A1 (en) | Production of ice 1 propenylphosphonic acid | |
| DE3230333C2 (en) | ||
| DE1545687B2 (en) | 1- (5'-Oxohexyl) -3,7-dimethylxanthine and process for its preparation | |
| DE2139084B2 (en) | Process for the preparation of 4,4-diphenyl-piperidines | |
| DE1670142A1 (en) | Process for the preparation of atropine, scopolamine and their N-substituted derivatives | |
| EP1019356A2 (en) | Method for producing 3-hydroxy-2-methylbenzoic acid | |
| AT273387B (en) | Process for the production of new cholesterol derivatives and their acid addition salts | |
| DE1620658C (en) | 1-Phenyl-4-aminopyrazole derivatives and processes for their preparation | |
| DE2412323B2 (en) | 1,2-Diphenyl ether derivatives, processes for their preparation and pharmaceuticals containing them | |
| DE2625671A1 (en) | PROCESS FOR MANUFACTURING OPTICALLY ACTIVE INDOLOCHINOLICINES | |
| EP0423595A2 (en) | Process for the preparation of 3-trichloromethyl pyridine | |
| DE3923389A1 (en) | METHOD FOR PRODUCING METHOXY ACETIC ACID | |
| EP0074488A1 (en) | 2-Azido-3-benzyloxy-propionic-acid benzyl ester, process for its preparation and its use | |
| DD210034A5 (en) | PROCESS FOR THE PREPARATION OF PIRBUTEROL | |
| DE1203253B (en) | Process for the preparation of basic fluorene derivatives and their salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| AK | Designated contracting states |
Designated state(s): AT BE CH DE FR GB IT LI NL SE |
|
| 17P | Request for examination filed |
Effective date: 19860228 |
|
| 17Q | First examination report despatched |
Effective date: 19870604 |
|
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| ITF | It: translation for a ep patent filed |
Owner name: SOCIETA' ITALIANA BREVETTI S.P.A. |
|
| AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE FR GB IT LI NL SE |
|
| REF | Corresponds to: |
Ref document number: 42550 Country of ref document: AT Date of ref document: 19890515 Kind code of ref document: T |
|
| GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) | ||
| REF | Corresponds to: |
Ref document number: 3569735 Country of ref document: DE Date of ref document: 19890601 |
|
| ET | Fr: translation filed | ||
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
| 26N | No opposition filed | ||
| ITTA | It: last paid annual fee | ||
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 19930125 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19930204 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19930209 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: AT Payment date: 19930210 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 19930211 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19930228 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 19930331 Year of fee payment: 9 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19930528 Year of fee payment: 9 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19940204 Ref country code: AT Effective date: 19940204 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19940205 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Effective date: 19940228 Ref country code: CH Effective date: 19940228 Ref country code: BE Effective date: 19940228 |
|
| BERE | Be: lapsed |
Owner name: LONZA A.G. Effective date: 19940228 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19940901 |
|
| GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 19940204 |
|
| NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Effective date: 19941031 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19941101 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
| EUG | Se: european patent has lapsed |
Ref document number: 85101150.2 Effective date: 19940910 |